US11390645B2 - Process for the preparation of 3β-hydroxy-17-(1H-benzimidazol-1-YL) androsta-5,16-diene - Google Patents

Process for the preparation of 3β-hydroxy-17-(1H-benzimidazol-1-YL) androsta-5,16-diene Download PDF

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US11390645B2
US11390645B2 US16/323,317 US201716323317A US11390645B2 US 11390645 B2 US11390645 B2 US 11390645B2 US 201716323317 A US201716323317 A US 201716323317A US 11390645 B2 US11390645 B2 US 11390645B2
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Francesco Barbieri
Roberto Lenna
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Industriale Chimica SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
    • C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • the present invention relates to the field of processes for the synthesis of active ingredients for pharmaceutical use, and in particular to a process for the industrial-scale preparation of 3 ⁇ -hydroxy-17-(1H-benzimidazol-1-yl)androsta-5,16-diene, also known as Galeterone, a compound useful for the treatment of prostate cancer, having the following formula:
  • Galeterone 3 ⁇ -hydroxy-17-(1H-benzimidazol-1-yl)androsta-5,16-diene was first described in the article “Three dimensional pharmacophore modeling of human CYP17 inhibitors. Potential agents for prostate cancer therapy”, O. Omoshile et al., J. Med. Chem. 2003, 46 (12), pages 2345-2351, in Figure 1 on page 2347, with the abbreviation VN/124-1*. The article does not report an experimental description of the preparation of the molecules object of the text, among which Galeterone, but refers to several other publications for the synthesis thereof.
  • the first synthetic step is described in “Novel C-17-Heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model”, V. D. Handratta et al., J. Med. Chem., 2005, 48 (8), pages 2972-2984.
  • This synthetic step consists of a Vilsmeier-Haack reaction which uses as a starting material 3 ⁇ -acetoxyandrosta-5-en-17-one (1) to yield 3 ⁇ -acetoxy-17-chloroandrosta-5,16-diene (2) and 3 ⁇ -acetoxy-17-chloro-16-formylandrosta-5,16-diene (3), as shown in the following scheme:
  • Intermediate (4) is then thermally deformylated using 10% palladium on carbon (Pd/C) as catalyst in an amount equal to 50% of the weight of intermediate (4):
  • the object of the present invention is to provide a synthesis route for the preparation of Galeterone that is simpler than the prior art processes and easily industrially applicable.
  • Galeterone a process for the preparation of Galeterone (6) comprising the reaction between 17-iodoandrosta-5,16-dien-3 ⁇ -ol (I) and benzimidazole to yield 3 ⁇ -hydroxy-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (6) (Galeterone):
  • the invention relates to separation by filtration from the reaction mixture of the compound obtainable by reaction of Galeterone with a physiologically acceptable organic or inorganic acid, this compound being useful for the purification of the desired product.
  • the Galeterone di-oxalate is separated by filtration.
  • the invention relates to salts obtained by reaction with Galeterone, which are employed for the purification thereof.
  • FIGS. 1, 2 and 3 show the results of HPLC analysis of products obtained according to the process of the invention.
  • the invention relates to a synthesis process of Galeterone (6) that is industrially applicable, comprising the steps described in detail hereinafter.
  • the step object of the invention consists in the reaction between 17-iodoandrosta-5,16-dien-3 ⁇ -ol (I) and benzimidazole in the presence of a base, of 8-hydroxyquinoline and cuprous iodide as catalysts to yield 3 ⁇ -hydroxy-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (6) also known as Galeterone:
  • Compound (I), 17-iodoandrosta-5,16-dien-3 ⁇ -ol, is a compound already known in the literature as an intermediate useful for the synthesis of Abiraterone acetate (II).
  • the reaction object of the present invention is carried out in a single organic solvent in the presence of benzimidazole, a base, cuprous iodide (CuI) and 8-hydroxyquinoline (organic ligand).
  • cuprous iodide copper is present in oxidation state +1, and the compound is normally indicated in the literature with the notation copper (I) iodide, wherein (I) indicates said oxidation state; in the present text and in the claims, only the name “cuprous iodide” or the formula CuI will be adopted to avoid confusion with compound (I), reagent in the reaction of the invention.
  • the organic solvent is selected among dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO) and 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pirimidinone (DMPU), and is employed in an amount between 5 and 20 times by volume, measured in ml, with respect to the weight in g of compound (I) loaded in the reaction (concentration (v/w).
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • DMSO dimethylsulfoxide
  • DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pirimidinone
  • the preferred solvent is dimethylformamide, and it is preferably used in a volume of between 5 and 10 times the weight (v/w) of compound (I).
  • the reaction temperature is of between 130° C. and 200° C.
  • the reaction temperature is between 140° C. and the boiling temperature of the reaction mixture as obtained after the addition of all components.
  • the reaction time is between 12 and 48 hours, preferably between 14 and 24 hours.
  • 8-hydroxyquinoline is used in an amount by weight of at least 1.8% with respect to the weight of compound (I) employed in the reaction. Preferably, an amount of 8-hydroxyquinoline equal to 3.6% of the weight of compound (I) loaded in the reaction is used.
  • the base employed may be selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium tert-butylate, potassium tert-butylate, sodium hydroxide and potassium hydroxide.
  • potassium carbonate K 2 CO 3
  • K 2 CO 3 potassium carbonate
  • the base is used in an amount by weight of at least 40%, and preferably at least 80%, with respect to the weight of compound (I).
  • Benzimidazole is used in an amount by weight of at least 30%, preferably at least 36%, with respect to the weight of compound (I).
  • the CuI catalyst is used in an amount by weight of between 1.2% and 5% of the weight of compound (I). Preferably, an amount by weight of CuI equal to 2.4% with respect to the weight of compound (I) is used.
  • the crude Galeterone obtainable from the reaction, carried out following the indications referred to above, can be purified by subjecting it to chromatography on silica gel and crystallizing it from organic solvent according to the common techniques known in the field of organic synthesis.
  • the inventors have surprisingly verified that the preparation of a Galeterone compound with an acid and its separation from the reaction mixture by simple filtration proves to be a particularly effective method for reaching, without resorting to chromatographic purifications, the levels of purity that an active ingredient requires to be used in pharmaceutical compositions.
  • acids physiologically acceptable inorganic or organic acids may be used, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, citric acid, lactic acid, oxalic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid and xinafoic acid; these acids can be used in anhydrous or hydrated form.
  • oxalic acid hydrate is used as acid, in amounts of at least two moles of acid per mole of Galeterone to be purified, obtaining Galeterone dioxalate, of formula:
  • the solution in which Galeterone has formed can be treated with a metal scavenging agent to eliminate any residual amounts of metal possibly present;
  • a metal scavenging agent suitable for the purpose are the products of the QuadraSil® family sold by Sigma-Aldrich, in particular the QuadraSil® MP product, consisting of spherical particles of macroporous silica functionalized to remove residual metals from products containing them (QuadraSil® is a registered trademark of the company Johnson Matthey).
  • Galeterone dioxalate takes place by reaction of Galeterone with oxalic acid in an organic solvent solution, from which the dioxalate separates as filterable solid.
  • the dioxalate is washed with a suitable solvent, e.g. toluene, methylene chloride or acetonitrile, dried (conveniently under reduced pressure), then re-suspended in a suitable organic solvent and treated with a base, added either pure or dissolved in a solvent, to recover pure Galeterone.
  • a suitable solvent e.g. toluene, methylene chloride or acetonitrile
  • the organic solvent in which the dioxalate is suspended is selected from xylene, toluene, cyclohexane, heptane, hexane, methylene chloride and acetonitrile, either pure or mixed with each other; the preferred solvent for this operation is pure methylene chloride.
  • the base is selected from sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, cesium carbonate and potassium carbonate, dissolved in water or in an alcohol such as methanol, ethanol, isopropanol; preferably it is used sodium hydroxide dissolved in methanol.
  • Chloroform-d D 99.8% atomic, containing 0.1% (v/v) tetramethylsilane (TMS) as internal standard; and Chloroform-d, “100%”, D 99.96% atomic, containing 0.03% (v/v) TMS.
  • the Milestone FlexiWAVE consists of a single microwave platform that, in combination with specific accessories, allows performing classic glassware and high-pressure synthesis.
  • MERCK TLC silica gel 60 F 254 Aluminum sheets 20 ⁇ 20 cm, code 1.0554.0001.
  • UV light at 254 and 366 nm.
  • UV cerium phosphomolybdic detector
  • Reaction sample 1 mL of reaction mixture in 2 mL water, extracted with 2 mL Isopropyl acetate. Deposited 1 ⁇ L.
  • Reference samples authentic samples identified by NMR and mass analyses.
  • each control is carried out by placing on the slide the reaction sample, the reference sample of the starting product and of the final product and an artificial mixture of reaction sample with the reference samples.
  • R f and RRT used in the examples indicate the delay factor in thin layer chromatography (TLC) and the relative retention time of a compound in high pressure liquid chromatography (HPLC), respectively.
  • the solid is dissolved in 3 L methylene chloride (CH 2 Cl 2 ), obtaining a biphasic system; 1 L water, 6 g carbon, 15 g dicalite are added and it is stirred for 10 minutes. It is filtered washing the filter with 300 mL CH 2 Cl 2 .
  • CH 2 Cl 2 methylene chloride
  • the phases are separated and the organic phase is washed with 300 mL of saturated aqueous solution of NaCl.
  • QuadraSil® MP 15 g QuadraSil® MP are loaded, it is stirred for 16 hours at 20 ⁇ T ⁇ 25° C., filtered on Millipore (JGWP) membrane, washing with 50 mL CH 2 Cl 2 .
  • JGWP Millipore
  • the organic phase is concentrated at 45° C. under reduced pressure distilling about 600 mL of solvent.
  • Oxalic acid dihydrate (190.06 g) is added to the remaining organic solution and it is stirred for 1 hour.
  • the resulting solid is filtered, washed with 300 mL CH 2 Cl 2 and dried at 45° C. and under reduced pressure for 16 hours.
  • bioxalate intermediate (6-OX) are suspended in 2324 mL CH 2 Cl 2 ; a saturated aqueous solution of NaHCO 3 is added dropwise to the suspension, obtaining the complete solubilization of the solid (pH of the aqueous phase equal to 4.7).
  • the biphasic solution is filtered, the phases are separated and the organic phase is washed with saturated aqueous solution of NaCl (300 mL).
  • the organic phase is concentrated by distilling to 2 ⁇ 3 of the volume, 700 mL t-butyl alcohol (tBuOH) are loaded; it is distilled up to complete elimination of CH 2 Cl 2 and of 120 mL tBuOH. Product precipitation is observed.
  • tBuOH t-butyl alcohol
  • a sample dried for analytical purposes and analyzed by HPLC shows a chromatographic purity of 99.55%; the HPLC graph is shown in FIG. 1 .
  • the product analyzed by HPLC shows a chromatographic purity of 99.73%; the HPLC graph is shown in FIG. 2 .
  • 190 g of product are solubilized under reflux with 1235 mL (6.5 volumes) of methyl alcohol, MeOH.
  • the crude sample is chromatographed on silica gel eluting with a mixture of methylene chloride/methanol 9/1.
  • the fractions containing product are concentrated to dryness and refluxed in pure methanol up to dissolution. After cooling, a crystalline solid is filtered which, dried to constant weight, turns out to be pure Galeterone (227 mg).
  • Example 2 The procedure of Example 2 is repeated with the only difference that DMSO (5 mL) is used as solvent instead of DMF.
  • Example 2 The procedure of Example 2 is repeated with the only difference that DMPU (5 mL) is used as solvent instead of DMF.
  • Example 2 The procedure of Example 2 is repeated with the only difference that 344 mg K 2 CO 3 (68.8% by weight with respect to compound (I)) is used.
  • Example 2 The procedure of Example 2 is repeated with the only difference that 258 mg K 2 CO 3 (51.6% by weight with respect to compound (I)) is used.
  • Example 2 The procedure of Example 2 is repeated with the only difference that DMA (5 mL) is used as solvent instead of DMF.
  • Example 2 The procedure of Example 2 is repeated but using 2.5 mL DMF solvent.
  • Example 2 The procedure of Example 2 is repeated but using 9 mg of 8-hydroxyquinoline.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
US16/323,317 2016-08-08 2017-08-08 Process for the preparation of 3β-hydroxy-17-(1H-benzimidazol-1-YL) androsta-5,16-diene Active 2039-02-28 US11390645B2 (en)

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Application Number Priority Date Filing Date Title
IT102016000083406 2016-08-08
IT102016000083406A IT201600083406A1 (it) 2016-08-08 2016-08-08 PROCESSO PER LA PREPARAZIONE DI 3β-IDROSSI-17-(1H-BENZIMIDAZOL-1-IL)ANDROSTA-5,16-DIENE
IT102016000121375 2016-11-30
IT102016000121375A IT201600121375A1 (it) 2016-11-30 2016-11-30 PROCESSO PER LA PREPARAZIONE DI 3ß-IDROSSI-17-(1H-BENZIMIDAZOL-1-IL)ANDROSTA-5,16-DIENE
PCT/EP2017/070124 WO2018029223A1 (en) 2016-08-08 2017-08-08 PROCESS FOR THE PREPARATION OF 3ß-HYDROXY-17-(1H-BENZIMIDAZOL-1-YL)ANDROSTA-5,16-DIENE

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EP4608841A1 (en) * 2022-10-25 2025-09-03 University of Maryland, Baltimore Salts of galeterone and salts of next generation galeterone analogs, and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006093993A1 (en) 2005-03-02 2006-09-08 University Of Maryland Novel c-17-heteroaryl steroidal cyp17 inhibitors/antiandrogens: synthesis, in vitro biological activities, pharmacokinetics and antitumor activity
WO2016119742A1 (zh) 2015-01-29 2016-08-04 苏州晶云药物科技有限公司 (3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的盐及其制备方法
WO2017140183A1 (zh) * 2016-02-19 2017-08-24 深圳市塔吉瑞生物医药有限公司 一种取代的甾体类化合物及其应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006093993A1 (en) 2005-03-02 2006-09-08 University Of Maryland Novel c-17-heteroaryl steroidal cyp17 inhibitors/antiandrogens: synthesis, in vitro biological activities, pharmacokinetics and antitumor activity
WO2016119742A1 (zh) 2015-01-29 2016-08-04 苏州晶云药物科技有限公司 (3β)-17-(1H-苯并咪唑-1-基)雄甾-5，16-二烯-3-醇的盐及其制备方法
WO2017140183A1 (zh) * 2016-02-19 2017-08-24 深圳市塔吉瑞生物医药有限公司 一种取代的甾体类化合物及其应用

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Berge et al. (Journal of Pharmaceutical Sciences, 1977, 66(1), pp. 1-19) . *
Clement, Omoshile O. et al., "Three Dimensional Pharmacophore Modeling of Human CYP17 Inhibitors. Potential Agents for Prostate Cancer Therapy", J. Med. Chem. (2003), vol. 46, No. 12, pp. 2345-2351.
Gerard A. Potter et al: "A Convenient, Large-Scale Synthesis of Abiraterone Acetate [3[beta]-Acetoxy-17-(3-Pyridyl) Androsta-5, 16-Diene], a Potential New Drug for the Treatment of Prostate Cancer", Organic Preparations and Procedures International (Feb. 1, 1997), vol. 29, No. 1, pp. 123-128.
Handratta Venkatesh D et al: "Novel C-17-Heteroaryl Steroidal CYP17 Inhibitors/Antiandrogens: Synthesis, in Vitro Biological Activity, Pharmacokinetics, and Antitumor Activity in the LAPC4 Human Prostate Cancer Xenograft Model", Journal of Medicinal Chemistry, American Chemical Society, US (Mar. 25, 2005), vol. 48, No. 8, pp. 2972-2984.
International Search Report dated Nov. 17, 2017 issued in PCT/EP2017/070124.
Vincent C. O. NJAR et al: "Discovery and Development of Galeterone (T0K-001 or VN/124-1) for the Treatment of All Stages of Prostate Cancer", Journal of Medicinal Chemistry (Mar. 12, 2015), vol. 58, No. 5, pp. 2077-2087.

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US20210284681A1 (en) 2021-09-16
RU2749134C1 (ru) 2021-06-04
CA3063339A1 (en) 2018-02-15
CA3063339C (en) 2024-05-28
ES2700901A2 (es) 2019-02-19
ES2700901R1 (es) 2019-03-04
ES2700901B2 (es) 2019-08-06
WO2018029223A1 (en) 2018-02-15

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